The natural history, prognosis and management of gastrinomas and other malignant pancreatic endocrine tumors (PET's) in patients without (sporadic disease) or with multiple endocrine neoplasia-type 1 (MEN1) is largely based on antedotal reports and small series. Gastrinomas are the most common symptomatic, malignant PET in patients with or without MEN1 and sufficient numbers of these patients have been entered into our protocols to allow systematic assessment. Studies are now underway, evaluating the natural history of these tumors including the presentation and initial diagnosis and definition of factors determining prognosis including attempting to identify molecular characteristics of the tumor that have prognostic significance. Our studies have identified a cohort of 25% of patients in whom the gastrinomas have aggressive growth and 25% who have multiple endocrine neoplasia type 1 (MEN1). The natural history of the latter group has been extensively analyzed this year. Prospective studies of MEN1/ZES patients show they frequently develop aggressive thymic carcinoids as well as meningiomas and also skin lesions (angiofibromas, collagenomas) that can be useful to diagnose this subgroup. Molecular studies of gastrinomas of patients with or without aggressive tumors during this year demonstrate loss of heterozgosity at 1q and on the X chromosome correlate with aggressive growth suggesting unknown tumor suppressor genes in these locations are important for tumor growth. Surgical studies completed during the year support a role for aggressive resection in patients with advanced, aggressive disease. A prospective study also provide strong evidence that routine duodenotomy at the time of surgical exploration is essential to find duodenal gastrinomas and will increase cure rate in these patients. The possible side-effects of longterm acid secretory control as well as long term hypergastrinemia are being examined including effects on vitamin B-12 and iron absorption as well as the development of gastric carcinoids and methods to identify these.